The invention relates to the role of dopamine D4 receptors in behavioral hyperactivity. In particular, it relates to treatments and therapies for inhibiting motor hyperactivity and attentional dysfunction associated with attention deficit-hyperactivity disorder (ADHD).
Attention deficit-hyperactivity disorder (ADHD) is a prevalent neuropsychiatric syndrome that affects 2%-5% of school-aged boys, an uncertain proportion of girls, and some adults. See R. A. Barkley, Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment (Guilford Press, New York, 1990). ADHD is characterized by excesses of hyperactive, inattentive and impulsive behavior. For several decades, the primary treatment available has been with psychostimulants for dopamine-enhancing effects, such as methylphenidate (Ritalin(copyright)) and amphetamines. Clinical use of these drugs is unsatisfactory owing to their short-lived benefits, risk of impaired sleep and appetite, of abnormal movements, and of abuse and illicit trade. See Goldman et al., JAMA, 279:1100 (1998).
An important action of stimulants is to enhance the functional activation of the amine neurotransmitter dopamine in the brain. See B. B. Hoffman and R. J. Lefkowitz in The harmacological Basis of Therapeutics, Chapter 10, Eds. Goodman and Gilman, McGraw-Hill, New York (1996). Dopamine (DA) is an important neurotransmitter involved in motor control, endocrine function, reward cognition and emotion. Dopamine modulates physiological processes though activation of five G-protein coupled receptors of the D1-like (D1 and D5) and the D2-like (D2, D3, and D4) receptor families. See K. A. Neve and R. L. Neve, in The Dopamine Receptors, K. A. Neve, R. L. Neve, Eds.; Humana Press, Totawa, N.J., 1997; pp. 27-76. D4 receptors have received much attention, in part, because some atypical antipsychotics, notably clozapine, bind to D4 receptors with higher affinity than to the more prevalent D2 receptors. See H. H. M. Van Tol et al., Nature 350:614 (1991); and Seeman et al. Neuropsychopharmacology 16:93 (1997).
Human D4 receptors occur in multiple forms with 2-11 copies of a 16-amino acid (48 base pair) sequence in the putative third intracellular loop of the peptide sequence. See Neve and Neve, supra. Several recent genetic studies suggest associations between polymorphic variants of the D4 receptor gene (D4DR) and ADHD. These studies are inconclusive, with various studies producing evidence for and against such an association, but converging evidence suggests that the D4 receptor has a role in exploratory behavior and as a genetic susceptibility factor for attention deficit disorder.
Tarazi et al., in xe2x80x9cDopamine D4 receptors: significance for psychiatry at the millenniumxe2x80x9d, Molecular Psychiatry, 4:529 (November 1999), identify a number of D4 receptor-selective antagonists and report on the behavioral effects of these agents in animal models for psychosis. Tarazi et al. report mixed results, with some antagonists showing an antipsychotic-like effect, while others did not.
Numerous investigations into the effects of selective D4 receptor agonists and antagonists on a variety of physiological and neurological functions have drawn a complex picture of the effects of D4 receptor-selective drugs and no clear picture has emerged as to the role of the D4 receptor in these processes. See Tarazi et al., supra; Patel et al., J. Pharmacol. Exp. Ther., 283(2):636 (November 1997); Bristow et al., J. Pharmacol. Exp. Ther., 283(3):1256 (December 1997); Feldpausch et al., J. Pharmacol. Exp. Ther., 286(1):497 (July 1998; P. A. Broderick and M. F. Piercey, J. Neuro. Transm., 105(6-7):749 (1998); Sanner et al., Bioorg. Med. Chem. Lett., 8(7):725 (April 1998); Jentsch et al., Psychopharmacology (Berl), 142(1):78 (Feb 1999); Belliotti et al., J. Med. Chem., 42(25):5181 (December 1999); and Okuyama et al., Life Sci., 65(20):2109 (1999).
The present invention is based on the discovery that motor hyperactivity can be dose-dependently reversed by D4 receptor-selective antagonists.
The invention features a method of inhibiting motor hyperactivity in a mammal exhibiting the symptoms of attention deficit-hyperactivity disorder (ADHD). The method includes administering to a mammal a dopamine D4 receptor-selective antagonist.
The D4 receptor-selective antagonists are selected from the group consisting of PNU-101958, RBI-257, NGD-94-1, L-745,870, L-750,667, PD-172,938, PNU-101387G, S-18126, NRA-0045, CP-293,019, YM-43611 AND YM-50001, the structures of which are shown in Table 1. Preferred D4 receptor-selective antagonist are CP-293,019 (7R,S-(4-fluoro-phenoxymethyl)-2-(5-fluoro-pyrimidin-2-yl)-octahydropyrido[1,2-xcex1]pyrazine) and L-745,870(3-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine, based on their high selectivity for D4 over D2 receptors.
The D4 receptor antagonist is administered intramuscularly, intravenously or subcutaneously to the mammal, and may be administered together with a pharmaceutically acceptable carrier. Preferred mammals include humans.
D4 receptor-selective antagonists are expected to be superior to the conventional therapies using psychostimulants in that they do not stimulate dopamine release or block its inactivation by reuptake or transport. This expectation is supported by the observation that D4 receptor-selective antagonists do not affect motor activity in healthy rats. See Bristow et al., supra; and Okuyama et al., supra. Furthermore, selectivity for D4 receptors over D2 receptors is desirable because interaction with D2 receptors causes unwanted extrapyramidal and neuroendrocrine side effects.
By xe2x80x9cD4 receptor-selective antagonistxe2x80x9d is meant an antagonist having more than 100, 200, 300, 500, 700, or 1,000 fold greater affinity for D4 receptors than for D2 receptors. Affinities for D4 and D2 receptors are determined using standard in vitro assays. See, for example, Den Hartog et al., U.S. Pat. No. 6,335,326, Patel et al., J. Pharmacol. Exp. Ther. 283:636-647 (1997), and Sanner et al., Bioorg. Med. Chem. Lett., 8(7):725 (April 1998).